PROJECT SUMMARY - UNIVERSITY OF NORTH CAROLINA-CHAPEL HILL, FROHLICH & SHIN Treating cognitive deficits in patients with disorders of the central nervous system such as epilepsy has remained a challenge of great clinical urgency. Modulating the temporal structure of cortical network activity with brain stimulation enables (1) the study of the causal role of oscillatory activity patterns in cognition and (2) the development of treatments for cognitive dysfunction by enhancement of pathologically impaired cortical oscillations. Both transcranial alternating current stimulation (tACS) and repetitive transcranial magnetic stimulation (rTMS) employ periodic stimulation waveforms that interact with endogenous cortical oscillations. Yet, due to the limitations of the non-invasive electrophysiology that can be performed in conjunction with such stimulation modalities in humans, it has remained unclear if and how these modalities indeed modulate local cortical oscillations and long-range functional connectivity in a targeted way. The long-term goal of our research is to develop novel brain stimulation treatments that engage network-level pathologies as targets for the treatment of cognitive impairment in neurological and psychiatric illnesses. The objective here is to elucidate how periodic stimulation modulates cortical oscillations associated with working memory by benefitting from the unique neurophysiological access to the human brain in epilepsy patients implanted with electrode grids for electrocorticography (ECoG). The working hypothesis is that periodic stimulation can enhance endogenous rhythmic activity underlying working memory and therefore modulate cognitive performance. The rationale for this work is that this approach in human patients will provide direct demonstration of target engagement by modulating cortical oscillations with periodic stimulation and therefore enable the development of individualized brain stimulation paradigms for the treatment of working memory impairment. The following two specific aims will be pursued to test the working hypothesis: (1) to modulate working memory performance by target engagement of local cortical oscillations with periodic intracranial stimulation through local electrode pairs, and (2) to modulate working memory performance by target engagement of inter-area functional connectivity with periodic intracranial stimulation through distant electrode pairs. Our approach is innovative since it combines the emerging framework of cortical oscillations as treatment target with the unique access to human brain function with ECoG by employing low-amplitude periodic stimulation through ECOG electrode grids for oscillation modulation. The significance of this works is that understanding how endogenous network activity shapes response to stimulation and how targeting of stimulation determines modulation of working memory will enable the development of (non-invasive) stimulation paradigms that directly target oscillation dynamics for the treatment of cognitive impairment in patients with neurological and psychiatric illnesses.